Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.
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ICR Authors
Authors
Kelly, MA
Caleshu, C
Morales, A
Buchan, J
Wolf, Z
Harrison, SM
Cook, S
Dillon, MW
Garcia, J
Haverfield, E
Jongbloed, JDH
Macaya, D
Manrai, A
Orland, K
Richard, G
Spoonamore, K
Thomas, M
Thomson, K
Vincent, LM
Walsh, R
Watkins, H
Whiffin, N
Ingles, J
van Tintelen, JP
Semsarian, C
Ware, JS
Hershberger, R
Funke, B
Caleshu, C
Morales, A
Buchan, J
Wolf, Z
Harrison, SM
Cook, S
Dillon, MW
Garcia, J
Haverfield, E
Jongbloed, JDH
Macaya, D
Manrai, A
Orland, K
Richard, G
Spoonamore, K
Thomas, M
Thomson, K
Vincent, LM
Walsh, R
Watkins, H
Whiffin, N
Ingles, J
van Tintelen, JP
Semsarian, C
Ware, JS
Hershberger, R
Funke, B
Document Type
Journal Article
Date
2018-03-01
Date Accepted
2017-10-24
Abstract
PurposeIntegrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.MethodsExpert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.ResultsAdjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.ConclusionThese adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.
Citation
Genetics in medicine : official journal of the American College of Medical Genetics, 2018, 20 (3), pp. 351 - 359
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
1098-3600
eISSN
1530-0366
Collections
Research Team
Molecular & Population Genetics